Total synthesis of 13beta-substituted gonapolyen-17alpha-ols



US. Cl. 260-397.5 4 Claims ABSTRACT OF THE DISCLOSURE In the totalsynthesis of 13 fi-substituted gonapolyen- 17a ols, 13-substituted8,14-secogona 1,3,5(10),9-tetraene-14,17-diones are reduced to give, asa racemic mixture, (2)13 substituted 17a-hydroxy-8,l4-secogona-1,3,5(10),9-tetraen-14-ones, which are readily optically separable. Naturaltype isomer of the racemic mixture is converted into natural type13-substituted gonapolyen-17a-ol, while the antipode of the natural typeisomer is convertible into starting 13 substituted 8,14secogona-1,3,5(),9- tetraene-14,l7-dione or into natural type13-substituted gonapolyen-17m-ol.

The present invention relates to a novel process for producing acompound having a gonapolyen-l7-one nucleus substituted in thel3-position by hydrocarbon residue, e.g. a lower alkyl, benzyl or phenylradical, and to novel intermediates therefor. More concretely, thisinvention relates to an improved total synthesis of a compound having a13-substituted gona-2,5(10)-dien-l7-one nucleus or a compound having al3-substituted g0na-1,3,5 (10)-trien- 17 -one nucleus and of novelintermediates therefor, e.g. a compound having a 13-substitutedgona-1,3,5(10),8-tetraen-17a-ol nucleus, a compound having a13-substituted gona-l,3,5(10),8,14-pentaen-17a-ol nucleus, a compoundhaving a 13-substituted 8,14-secogona-1,3,5(10),9-tetraen- 17a-Olnucleus, all of which have a hydrocarbon residue as a substituent at the13-position.

The reason why partial synthesis has overwhelmed total synthesis inindustrial production of steroids is due mainly to difiiculty intreating a number of stereoisomers which are concomitantly producedeither at the cyclization to form the steroid skeleton or at thesaturation of the internuclear unsaturated bonds.

Recently, Hughes and Smith reported a stereo-selective total synthesisof (i)-estrone, starting from S-(m'methoxyphenyl)pent-1-yne via (i-estra-1,3,5 10) ,8,14-pentaen-I7-onesee Chemistry and Industry, 1960,pages l022-1023 with reference to Proceedings of Chemical Society, 1960,pages 74-75. Furthermore, more improved total syntheses of19-nor-steroids have been reported independently by Smith et al.,(Experientia, 19, 394-396 (1963, No. 8), Windholz et al. (Journal ofOrganic Chemistry, 28, 1092-1094 (1963)), Miki et a1. (Proceedings ofthe Chemical Society, May 1963, 139) and Crispin et al. (ibid, January1963, 22). Although these processes "United States Patent 0 ICC broughta hope of realizing an industrial total synthesis of steroids, theprocess is still accompanied by some difficulties, the most serious oneof which is that these processes are accompanied necessarily with theproduction of useless stereoisomers.

The present invention is based upon the unexpected discovery that acompound (III)--(references in Roman numerals refer to the reactionchart, infra) having a 13- substituted 8,14 secogona-1,3,5(l0),9-tetraene-14,l7-dione nucleus is readily reduced to producepredominantly (i)17ot hydroxy 13 substituted 8,14 secogona-1,3,5(10),9-tetraen-14-ones as a racemic mixture of a compound (IV-I) havinga ()17a-hydroxy-13-substituted- 8,14-secogona-l,3,5(10),9-tetraen-14-onenucleus and of its antipode (IV-II) having a(+)17a-hydroxy-13-substituted 8,14 secogona-1,3,5(10),9-tetraen-14-onenucleus. The compounds (IV-I) can be converted into natural typegona-1,3,5(10)-trien-17-ones or gona-2,5(l0)-dien- 17-ones, while theantipodes (IV-II) can be converted into antipodes of the natural typegona-1,3,5 (10)-trien-17-ones or gona-2,5(10)-dien17-ones. Moreover,compounds (IV- II) are recoverable as gona-1,3,5(10 ),9-tetraen-14,17-diones (III) by oxidation of (IV-H) or are readily convertible togona-1,3,5(10),8,14-pentaen-l7a-o1s (V); see aforesaid chart.

A principal object of the present invention is therefore to embody aprocess for producing compounds having a 17a hydroxy 13 substituted8,l4-secogona-1,3,5 (l0),9-tetraen-l4-one nucleus, which are convertibleinto natural type l9-nor-steroids.

Another object of this invention is to provide a process for producing acompound (III) having a l3-substituted- 8,l4-secogona1,3,5 (10),9-tetraene-l4,17-dione nucleus by oxidizing a compound (IV-II) having a(+)13-substituted 17a-hydroxy-8,14-secogona-1,3,5(10),9-tetraen-14- onenucleus.

A further object of this invention is provide a process for producing acompound (V) having a(+)l3-substituted-gona-1,3,5(l0),8,14-pentaen-17a-ol nucleus from acompound (IV-J1) having a 13-substituted-17a-hydroxy8,14-secogona-l,3,5(10),9-tetraen-14-one nucleus.

CH=CH2 wherein R is hydroxyl, etherified hydroxyl radical (e.g. methoxy,ethoxy, benzyloxy), or esterified hydroxyl radical (e.g. acetyloxy,nicotinoyloxy) and may be substituted, for example, at one or more ofthe positions 3, 4, 5, 7 and 8 in the tetralin skeleton, by ahydrocarbon residue with 1 to 7 carbon atoms such as lower alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl), phenyl orbenzyl, and/or at one or more of the positions 5, 6, 7 and 8 in theskeleton, by a hydroxyl group, an etherified hydroxyl group (eg methoxy,ethoxy, n-propoxy and n-butoxy), an esterified hydroxyl group (e.g.acetoxy, propionyloxy and benzoyloxy), a halogen (e.g. fluorine andchlorine), a thio group (e.g. mercapto, methylthio, ethylthio andacetylthio) and an acyl group (e.g. acetyl, propionyl and benzoyl).

The 2-substituted cyclopentane-1,3-diones have a general structurerepresented by the formula:

wherein R the substituent at position 2, is a hydrocarbon residue, whichis exemplified by lower alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl and isobutyl), phenyl and benzyl. One to three of the hydrogenatoms at the positions 4 and 5 of these 2-substituted cyclopentane-1,3-diones can further be replaced by one to four hydrocarbon residues asexemplified above.

The first step of the present invention comprises a selective reductionof a compound having a 13-substituted- 8,14-secogona-1,3,5(),9-tetraene14,17 dione nucleus (III), to produce a compound having a(:)13-substituted-17a-hydroxy 8,14 secogona-l,3,5(10),9-tetraen- 14-onenucleus (IV) which is substantially a mixture of (IV-I) and (IV-II).

A means for converting compound (III) to compound (IV) is realized byreduction of the former with a specified reducing agent.

Reducing agents applicable to the reduction of (III) to thecorresponding tetraenols (IV) must be capable of reducing a carbonyl toa carbinol without attacking carbonto-carbon double bonds. Preferablyreducing agents include metallic hydrides and aluminum trialkoxides withup to 4 carbon atoms, for example, alkali metal boron hydrides (e.g.lithium boron hydride, sodium boron hydride and potassium boronhydride), alkali metal aluminum hydrides (e.g. lithium aluminum hydride,sodium aluminum hydride and potassium aluminum hydride), diethylaluminum hydride and aluminum isopropoxide. The reaction is usuallycarried out in a solvent. Desirable solvent can be selected from usualorganic solvents so long as the solvent does not disturb the reaction,and may be exemplified by methanol, ethanol, n-propanol, isopropanol,n-butanol, tetrahydrofuran, dioxane, ether, petroleum ether, chloroform,benzene and toluene. The hydridetype reducing agents as exemplifiedabove are generally allowed to react With the compounds (III) at arather low temperature, e.g. below an ambient temperature (about 2025C.) but higher than about -60 C., while the reaction of thealkoxide-type reducing agents is desirable accelerated by heating and isusually carried out in boiling isopropanol or ethanol which acts bothsolvent and reactant.

The compounds (IV) thus produced are new and useful for the purpose ofthe present invention, and have the general structure shown by theformula:

to il) wherein each of R and R has the same meaning as defined above inconnection with Formulae I and II, and may have a substituent orsubstituents corresponding to the starting compounds (I) and (II). Theproduct (IV) prepared by the above step substantially comprises aracemic mixture consisting of the following two stereoisomers (which aremirror images of each other):

Therefore, in order to obtain an optically active product, racemicresolution is required. Especially in the present invention, it isoptimal to subject the above mentioned racemic mixture of compounds(IV-I) and (IVII) to racemic resolution, because the undesired isomer isconverted to a compound having a13-substituted-8,14-secogona-1,3,5(10),9-tetraen-l4,17-dione nucleus(III) or to a desired compound having a 13-substituted-gona-1,3,5(10),8,14-pentaen-17a-ol nucleus, both methods being disclosedhereinbelow. The racemic resolution mentioned hereinafter is applicableto any of the compounds respectively having such a nucleus asa(i)13-substitutedgona-l,3,5(10),8,l4-pentaen-17a-ol nucleus (V), a (i)13-substituted-gona 1,3,5(10),8 tetran-17ot-ol nucleus (VI), a (:)13-substitutedgona-1,3,5(10)-trien-17u-ol nucleus (VII) and a)13-substituted-gona-2,5(10)- dieH-t-O1 nucleus. But, in general, theracemic resolu-l tion should be effected as early as possible.

In the method of the present invention, racemic resolution is carriedout easily by utilizing the generally existing 17 a-hydroxyl group. Onemeans for effecting the racemic resolution is through an opticallyactive ester of the steroid and another means is enzymic hydrolysis ofan acylated derivative of the product.

In the first means of racemic resolution, the l7a-hydroxy steroids areallowed to react with an optically active acid or its acid halidee.g.l-methoxyacetic acid or its chloride or bromide-40 give a mixture of thecorresponding diastereomers, separating respective diastereomers asusual, e.g. by fractional recrystallization, followed by hydrolysis torecover the optically active 17a-ols. In place of acylation with anoptically active acid, the 17a- 01 may be esterified with a dibasice.g.succinic acid,

phthalic acid or sulfobenzoic acid-by means of its reac- J tivederivative such as an anhydride or a chloride to give the correspondinghemiester, followed by the formation of salts with an optically activebase such as ephedrine, strychnine and brucine.

In an alternative procedure for the racemic resolution, the l7a-0l isacylated in conventional manner to give the 17-acylate such as acetate,acetoacetate, glycinate, diethylaminoacetate, hemisuccinate andhemiadipate, and the resulting acylate is subjected to an enzymatichydrolysis in an aqueous medium containing hydrolase which may beexemplified by diastase, lipase and trypsin. The technique of effectingthe enzymic hydrolysis is set forth in US. Pat. No. 3,094,465 and thehydrolysis and the recovery of steroids can be carried out after themanner described in the said patent. Some microorganisms capable ofproducing said hydrolase may directly be brought into contact with thel7-acylates. Such microorganisms include, for example, those belongingto the general R-hizopus and'Aspergillus.

Thus-obtained compounds having a13-substitutedl7a-hydroxy-8,14-secogona-1,3,5(10),9-tetraen 14 onenucleus are exemplified as follows:

(+) or 17 a-hydroxy-3-methoxy-8, l4-secoestra- 1,3,5 10),9-tetraen-14-one; 1

( or 17a-hydroxy-3-ethoxy-8,14-secoestra- 1,3,5 l) ,9-tetraen-14-0ne;

( or l7u-hydroxy-13-ethyl-8,14-secogona- 1,3,5 (10) ,9*-tetraen-14-one;

(+) or 17m-hydroxy-13-isopropyl-8,l4-secogona- 1,3,5 l0),9-tetraen-l4-one;

(+) or Nix-hydroxy-13-benzyl-8,14-secogona- 1,3,5 l0) ,9-tetraen-l4-one;

(+) or 17a-hydroxy-13-phenyl-8,14-secogona- 1,3,5(10),9-tetraen-l4-one;

(1+) or 17a-hydroxy-3-methoxy-13-ethyl-8,14-

secogona-1,3,5(10),9-tetraen-l4-one;

(+ or 17u-hydroxy-3-methoxy-13-n-propyl-8,14-

secogona-1,3,5 1 0) ,9'-tetraen-14-one;

(+) or 17a-hydroxy-3-methoxy-l3-isopropyl-8,14-

secogona-1,3,5 l0) ,9-tetraen-14-one;

(+) or 17 a-hydroxy-3-methoxy-1 3-phenyl-8, 14-

secogona-1,3,5(),9-tetraen-14-one;

(+) or 17u-hydroxy-3-methoxy-13-benzyl-8,14-

secogona-1,3,5(10),9*tetraen-14-one;

(+) or ()17u-hydroxy-8,14-secoestra-1,3,5(10),9-

tetraen-14-one;

The second step of the present total synthesis is an intramolecularcyclization of the compounds (IV-I), resulting in closure of the ring Cto give compounds having a 13-substituted-17m-hydroxy-gona-1,3,5(10),8,14-pentaen-17-one nucleus (V).

The cyclization is accelerated by the use of an acid catalyst, which isexemplified by inorganic acids or their anhydrides (e.g. hydrochloricacid, sulfuric acid, phos- Nomn.T-he compound here corresponds to thenatural type steroid and the compound is (unnatural) anrtipode thereof.

phoric acid, phosphorus pentoxide and polyphosphoric acid), hydrogensalts or partial esters of these polybasic inorganic acids (e.g. sodiumhydrogen sulfate, monosodium dihydrogen phosphate and monomethylsulfate), their pyridine complexes (e.g. pyridine-hydrobromic acidcomplex), sulfonic acids (e.g. methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid and toluenesulfonic acid), sulfonatedstyrene-type cation exchange resins, so-called Lewis acids (e.g.aluminum chloride, boron trifluoride and tin chloride) and silica gel.

This reaction does not require any solvent, However, the reaction can beeffected more smoothly by the use of a suitable solvent, such e.g. asbenzene, toluene, xylene, tetrahydrofuran, dibutyl ether, methanol,ethanol and propanol. This reaction is also accelerated by heat andtakes place easily under mild heating. If necessary, the reaction may becarried out in the neighborhood of C. or higher.

The reaction in this step takes place via l4-hydroxygone-1,3,5(l0),9-tetraen-l7a-ols as intermediates, because suoh mild conditions asthe use of silica gel often cause the production of these intermediates,which are readily converted by further contact with a rather drasticacid catalyst to yield the desired compounds (V).

The resulting compound having a 13-substituted gona-1,3,5(10),8,14-pentaen-17u-ol nucleus (V) have the general structureshown by the formula:

wherein each of R and R is as defined above, and include the substituentor substituents corresponding to the starting compounds, when the latterare substituted; that is, at any of the positions 1, 2, 3, 6, 7, 15 and16, one or more of the hydrocarbon residues exemplified with regard tocompounds (I) and (II), and/ or at any of the positions 1, 2 and 3hydroxyl, etherified hydroxyl, esterified hydroxyl, halogen and thio, asexemplified with regard to compounds (I). Among them, those especiallyadvantageous for the purpose include, for example:

(+) or ()3-methoxyestra 1,3,5(10),8,l4-pentaen-17a- 1 NoTn.The compoundhere corresponds to the natural type steroid and the compound is(unnatural) antipode thereof.

All the exemplified compounds show characteristic ultraviolet absorptionbands in the range of the wave length of about 310 millimicrons.

The compounds (V) can be converted stereoselectively and exclusively tothe corresponding 13-substituted gona- 1,3,5(l)8-tetraen-l7a-ols (VI) inwhich the hydrogen attached to the position 14 is oriented torat-configuration; that is, the same configuration as estrogenicsteroids obtained from natural sources.

The conversion of compounds (V) to compounds (VI) is convenientlyeffected by so-called catalytic reduction. For this purpose, Raneynickel or palladium catalyst is preferably used. The reaction can becarried out in a suitable solvent which is exemplified by dioxane,tetrahydrofuran, ether, methonal, ethanol and acetic acid. The reactionusually takes place at ambient temperature (15 to 30 C.); but, ifrequired, it may be carried out at an elevated or lowered temperature.At any event, too drastic conditions should be avoided for thisreaction, since further hydrogenation may take place at the positions 8and 9 which may result in opposite configuration of the hydrogen at theposition 8 in the product.

The compounds (VI) thus produced are also new and useful for the purposeof the present invention and have the general formula shown by theformula:

wherein each of R and R is as defined above. They may also contain, forexample, at any of the positions 1, 2, 3, 6, 7, 15 and 16, one or morehydrocarbon residues as described with regard to compounds (I) and (H),and/or at any of the positions 1, 2 and 3, hydroxyl, etherified hydroxyl(e.g. methoxy, ethoxy, propoxy and butoxy) as Well as esterifiedhydroxyl, halogen, and thio, as described with regard to compounds (I).Among them, the ones especially advantageous for the purpose include,for example:

(+) or 3-methoxyestra-1,3,5(10),8-tetraen-17a-ol; 1

(+) or ()3-ethoxyestra-1,3,5( ),8-tetraen17u-ol;

(+) or ()13-ethylgona-l,3,5(10),8-tetraen-17u-ol;

(+) or ()13-isopropylgona-1,3,5(10),8-tetraen-17u-ol;

(+) or ()13-phenylgona-1,3,5(10),8-tetraen-17a-ol;

(+) or l3-benzylgona-1,3,5(10),8-tetraen17a-ol;

(+) or ()3-methoxy-13-ethylgona-1,3,5(10),8-tetraen- 17a-ol;

(+) or ()3-methoxy-13-isopropylgona-1,3,5(10),8-tetraen-17a-ol;

(+) or ()3 methoxy 13 phenylgona -1,3,5(10),8

tetraen-17ot-ol;

(+) or ()3 methoxy 13 benzylgona 1,3,5(10,8-

tetraen-17a-ol;

(+) or ()estra-1,3,5(10),8-tetraen-17a-ol;

All the exemplified compounds show characteristic absorption bends inthe range of the wave lengths of about 273-281 millirnicrons.

1 No'rE.The compound here corresponds to the natural type steroid andthe compound is (unnatural) a pode thereof.

Thus-prepared compounds (VI) are subjected to a further reduction tosaturate the double bond at the position 8.

The reduction is preferably carried out by allowing an alkali metal toreact with the compounds (VI) in liquid ammonia. The alkali metal may belithium, sodium and potassium, for example. The reaction is carried outin liquid ammonia or its mixture with an inert solvent. The inertsolvents for the purpose include, for example, ether, dioxane andtetrahydrofuran. Since the agent is rather violent, the reaction isusually brought about at a lowered temperature, i.e. below ambienttemperature to about 30 C.

In this way, there are produced with a good overall yield l3-substitutedgona-1,3,5(10)-trien-l7a-ols (VII), which include estradiol or itsrelated compounds as well as a number of novel compounds which also showestrogenic activity, and which have the general structure shown by theformula:

(VII) wherein each of R and R is as defined above, and may have the samesubstituent or substituents as in compounds (VI) used for the productionthereof.

Thus-prepared compounds (VII) can be reduced to saturate the double bondat aromatic ring to produce a compound having a13-substituted-gona-2,5(10)-dien-17aol nucleus (VIII). The reduction maypreferably be carried out by allowing an alkali metal to react with thecompounds (VII) in liquid ammonia containing a proton source such asalcohols having up to 6 carbon atoms, e.g. methanol, ethanol,tertiary-butanol, etc., other conditions being the same as the above. Inthe same manner as this reaction, the compound having a13-substituted-1,3,5( 10), 8-tetraen-17a-ol (VI) nucleus may also beconverted to the same product (VIII), the double bond at the position 8as well as the double bond on the aromatic ring being saturated.

Thus-obtained trienols (VII) and dienols (VIII) can be respectively ledto a compound having a 13-substitutedgona-trien-17-one nucleus (X) andto a compound having a 1B-substituted-gona-dien-17-one nucleus (IX),both being the same configuration as estrogenic steroids obtained fromnatural sources.

The reaction may be carried out by e.g. Oppenauer oxidation employingaluminum isopropoxide, aluminum ethoxide, aluminum phenoxide,pyridine-chromic acid anhydride, etc., by an oxidation employingpyridine-chromic acid anhydride ordimethylsulfoxide-dicyclohexylcarbodiimide, by an oxidation employingmicroorganisms, etc. These reactions are preferably carried out underneutral or alkaline conditions.

All reactions mentioned hereinbefore are applicable to racemic mixturesas well as to optical isomers. However, as already mentionedhereinbefore, it is preferable to subject the compound having a(1)13-substitutedl7ot-hydroxy-8,14-secogona-1,3,5( 10) ,9-tetraen-14-onenucleus (IV) to optical resolution, for the purpose of recovering theunnatural type compound having a (+)13 substituted-18,14-secogona-1,3,5(l0) ,9-tetraen-l7a-0l nucleus (IV-II).

Such recovering process is carried out by allowing said compound (IV-II)to react with an oxidizing agent, whereupon a compound having a13-substituted-8,l4-secogona-1,3,5(10),9-tetraene-14,l7-dione nucleus(III) is obtained. Oxidizing agents applicable to this reaction must becapable of oxidizing hydroxyl radical to oxo radical without attackingcarbon-to-carbon double bond. Preferable oxidizing agents include, for'example chromic acid, aluminum alkoxide and ketones (Oppenaueroxidation), dimethylsulfoxide-dicyclohexylcarbodiimido, etc. Thusobtained secodiones (HI) may be used as the starting materials of thepresent process.

Alternatively, the compound having a (+)13-substituted 8,14secogona-1,3,5(10),9-tetraen-17a-o1 nucleus (IV-II) may be converted toa compound having a 13-substituted-gona-1,3,5( 10) ,8,14-pentaen-17a-olnucleus (V), in which the substituent attached to the position 13 isoriented to B-configuration, that is, the same configuration asestrogenic steriods obtained from natural sources. The conversionprocess comprises the following steps:

(1) Allowing the secotetrane-17a-ol compounds (IV- II), to react with aconventional acylating agent to produce a compound having a(+)l3-substituted-17a-acyloxy 8,14 secogona-1,3,5(10),9-tetraen-14-onenucleus (XI).

(2) Reducing the so-obtained (+)l7u-hydroxy-secotetraenones (XI), with ametallic hydride compound to produce a compound having a(+)13-substituted-17aacyloxy-8,l4-secogona 1,3,5(10),9-tetraen-14-olnucleus (XII). The reaction conditions of this step are the same asemployed in the reducing process of secodions (III) to seco-l7a-ols(IV).

(3) Thus-obtained 17a-acyloxy-seconeno1 (XH) is allowed to contact withacid catalyst to produce a compound having a(+)13-substituted-17a-acyloxy-9,14-oxido 8,14secogona-1,3,5(10),9*tetraen nucleus (XIII). The reaction conditions ofthis step are similar to those employed in the cyclization process ofsecotetraenols (IV) to obtain pentaenols (V).

(4) Thus-obtained l7a-acryloxy-oxide (XIII) is subjected to hydrolysisto produce a compound having a 13substituted-9,14-oxido-8,14-secogona-1,3,5 l),9- tetraen-17-ol nucleus(XIV). For the hydrolysis, there are employable any conventionalconditions for hydrolysis, for example, in the presence of alkali metalhydroxide (e.g. sodium hydroxide, potassium hydroxide), hydrolyase (e.g.maltase, diastase), and so on.

Thus-obtained oxido-tetraenol (XIV) is subjected to oxidation to producea compound having a (-)13 substituted-9,14-oxido-8,14-secoestra- 1,3,5l0) ,9-tetraen- 17-one nucleus (V). This reaction is carried out under10 the same conditions as mentioned above in the process of oxidizingtrienols (VII) or dienols (VIII) to trienons (X) or dienone (I)respectively and the recovering process oxidizing secotetraenols (IV-II)to secodiones (III).

(6) And finally thus-obtained oxiclo-17-one (XV) is subjected to contactwith acid catalyst to produce a compound having a13-substituted-gono-l,3,5(l0),8,14- pentaen-l7a-ol nucleus. Thiscyclization reaction is carried out under the same conditions asemployed in the process subjecting the secotetraenols (IV-I) to cyclizeto pentaenols (V).

The following reaction scheme diagrammatically visualizes the severalconversions according to the present invention.

The 13-substituted-gonatrien-17-ones (X) include estrone which is knownand useful as estrogenic hormone in itself or as an intermediate forsynthesis "of many useful l9-nor-steroids. The 13 substituted-gona 1,3,5(10)- trien-17u-ols (VI) includes a-estradiol which is also known anduseful as an inhibitor of the anterior pituitary gland or as anintermediate for synthesizing many useful 19- nor-steroids. The processof the present invention thus provides a new and improved means for thetotal synthesis of inter alia estrone or a-estradiol, because of itshigh over-all yield at every stage of the reaction sequence and becauseof convertibility of starting material (III) into natural type steroids,e.g. estrone or a-estradiol.

The 13-substituted-gonatrien-l7 -ones (X) and the 13-substituted-gonatrien-l7a-ols (VII) also include novel compounds,especially where the substituent at 13-position is e.g. ethyl, propyl,isopropyl, butyl, isobutyl, phenyl or benzyl. These novel compounds aswell as the 13-substituted gonapentaenor tetran-17a-ols (V) or (VI) showe.g. activity in lowering cholesterol level in the blood.

At the same time, the novel 13-substituted-17a-hydroxy-8, 14-secogona-1,3,5(10),9 tetren-l4-ones (IV), optically active isomersthereof, the 13-substituted gona- 1,3,5(10),8, l4-pentaen-17a-ols (V),the lit-substituted gona-1,3,5(10),8-tetraen-17a-o1s (VI) and otheroptically active 8,14-s'eco-steroids (XI), (XII), (XIII), (XIV) and (XV)are all useful as intermediates for the total synthesis of thefuseful19-nor-steroids. I

It is to be understood that the :following examples are solely for thepurpose of illustration and not to be construed as limitations of thisinvention, and that many variations may be resorted to without departingfrom the spirit and scope of this invention. In examples, g. and ml. aregram(s) and milliliter(s), respectively. Temperatures are uncorrected,and percentages are all on p the weight basis.

13 EXAMPLE 1 1) (i 3 -methoxy-17u-hydroxy-8,14-secoestra- 1,3,5 10,9-tetraen-l4-one To a solution of 2 g. of 3-methoxy-8,14-secoestra-l,3,5(l),9-tetraene-14,l7-dione in 100 ml. of methanol there is added 0.08g. of sodium borohydride under icecooling and the mixture is stirredunder the same conditions. After 2 hours, the reaction solution isshaken with a mixture of water and ether, and the ether layer is washedwith water and dried, followed by evaporation of the solvent to give 1.8g. of (:-)3-methoxy-17a-hydroxy-8,14-secoestra-1,3,5(10),9-tetraen14-one. The product is recrystallized froma mixture of ether and hexane to give pure product melting at 74 C.

Elementary analysis-Calculated for C H O (percent): C,76.00; H, 8.00.Found (percent): C, 76.27; H, 7.92.

Ultraviolet absorption:

Mail? 266 mu (e-19300).

(2-1) (i)3-methoxyestra-l,3,5(l0),8,14-pentaen-17a-ol To a solution of1.7 g. of (i)3-methoxy-17a-hydroxy- 8,l4-secoestra-1,3,5(l0),9-tetraen-14-one in 50 ml. of methanol, there is added 5 ml. of6-normal hydrochloric acid, and the mixture solution is left standing atroom temperature for 2 hours, followed by shaking with a mixture ofwater and ether. After the ether layer is washed with an aqueoussolution of sodium hydrogen carbonate and then with water, it is driedand subjected to evaporation to remove the solvent. The residue ischromatographed on a column packed with 80 g. of silica gel and 1.2 g.of (2)3 methoxy 9,14 oxido-8,14-secoestra- 1,3,5()-trien-17-one isobtained from the eluate with a mixture of benzene and ether (9:1).Melting point: 83 C.

Elementary analysis.-Calculated for C H O (percent): C, 76.00; H, 8.00.Found (percent): C, 75.88; H,

Ultraviolet absorption:

ethanol hm.

In,u(e); 255 (8850), 275 (1690), 282 (1665).

Infrared absorption:

nuiol mnx.

ethanol mnx.

m,u(e). 311 (20000).

Infrared absorption:

totraeliloromethnne mnx.

cm.- 3400 (OH). (22) (1- 3-methoxyestra-l,3,5 (10),8, l4-pentaen-l7a-0lTo a solution of 1 g. of -)3-methoxy-17a-hydroxy-8,14-secoestra-l,3,5(l0),9-tetraen-l4-one in 50 ml. of methanol there isadded 7 ml. of concentrated hydrochloric acid and the mixture isrefluxed for 30 minutes, followed by shaking with a mixture of water andether. After the ether layer is washed with an aqueous solution ofsodium hydrogen carbonate and then with water and dried, it is subjectedto evaporation to remove the solvent to give 0.8 g. of(:L)3-methoxyestra-1,3,5(10),8,14- pentaen-17a-ol as a yellowish oil.

(3) (i 3-methoxyestra-1,3,5( 10) ,8-tetraen-17a-ol A solution of 0.9 g.of (i)3-methoxyestra-1,3,5 (10), 8,14-pentaen-17a-o1 in ml. of dioxaneis subjected to catalytic hydrogenation in the presence of 1 g. of Raneynickel. Filtering off the catalyst, the filtrate is condensed underreduced pressure to give a residue, from which 0.5 g. of crystals of(i)3-methoxyestra-1,3,5(10),8-teraenl7a-ol are obtained. The crystalsare recrystallized from ethyl acetate. Melting point: 161 C.

Elementary analysis.-'Calculated for C H O (percent): C, 80.28; H, 8.45.Found (percent): C, 79.97; H, 8.41.

Ultraviolet absorption:

852"" m (e): 277 (15700). (4) (i 3-methoxyestra-l,3,5(I10) -trien-17u-o1To a solution of 0.4 g. of (i)3-methoxyestra-1,3,5(l0), 8-tetraen-17a-olin a mixture of 70 ml. of liquid ammonia, 20 m1. of dioxane and 40 ml.of ether, 0.7 g. of metallic potassium, there is added under cooling at50 C. and the mixture is stirred for 2 hours under the same conditions.To the reaction solution, there is added 2 g. of ammonium chloride andthen the resultant solu tion is left standing at room temperature toremove ammonia. To the residue, there is added water and the mixture isextracted with ether. After the ether layer is washed With water anddried, it is condensed to give a residue, which is recrystallizedfromhexane to obtain 0.2 g. of (i)3-methoxyestra-1,3,5(l0)-trien-l7aol ascrystals melting at 94 C.

Elementary analysis.-Calculated for C H O (percent): C, 79.72; H, 9.09.Found (percent): C, 79.98; H, 9.15.

Ultraviolet absorption:

ma E 280 (1980), 288 1900 (5) (i)3-methoxyestra-1,3,5(10)-trien-17a-oneTo a solution of 0.2 g. of (i)3-methoxyestra-1,3,5- (l0)-trien-l7a-ol in10 m1. of acetone, there is added under stirring 0.2 ml. of a solutionin which 26.72 g. of chromic anhydride and 23 ml. of concentratedsulfuric acid are dissolved in water to give ml. of total volume, andthe mixture solution is kept standing for 20 minutes at roomtemperature. To the reaction solution, there is added water toprecipitate crystals, which are recrystallized from methanol to give0.15 g. of -)3 methoxyestra-1,3,5(10)-trien 17 one. Melting point: C.

(6) (:)3-methoxyestra-2,5(10)-dien-l7a-ol To a solution of 1 g. of(i)3-methoxyestra-1,3,5(10), 8-tetraen17a-ol in a mixture of 50 ml. ofdioxane, 50 ml. of ether and ml. of liquid ammonia, said solution beingcooled at 50 C., there is added 2 g. of metallic lithium and the mixtureis stirred. After 30 minutes, 50 ml. of ethanol is added dropwise to thereaction solution and then the resultant solution is left standing atroom temperature to remove ammonia. The residue is shaken with a mixtureof water and ether, and the ether layer is, after washed with water anddried, subjected to evaporation to remove the solvent to give crystalsof (i) 3-methoxyestra-2,5(10)-dien-17a-ol, which are recrystallized froma mixture of ether and hexane to give colorless needles melting at 119C. Yield: 0.6 g.

(7-1) (i) 3-methoxyestra-2,5( 10) -dien-17-one In a solution of 1.5 ml.of benzene, 1.5 ml. of dimethylsulfoxide, 0.8 ml. of pyridine and 0.04ml. of trifluoroacetic acid, there is dissolved 0.2 g. of (i)3-methoxyestra 2,5 (10)-dien-17a-ol and to the resultant solution there isadded 0.62 g. of dicyclohexylcarbodiimide, followed by allowing themixture to stand for 6 hours at room temperature. Then, to the reactionmixture is added a solution of 25 ml. of ether, 0.3 g. of oxalic acidand 6 ml. of methanol, and the mixture solution is left standing. After30 minutes, the produced dicyclohexylurea is filtered off and the etherlayer is separated from the filtrate. After the ether layer is Washedwith an aqueous solution of sodium hydrogen carbonate and then Water,and dried, it is subjected to evaporation to remove the solvent and theresidue is recrystallized from ethanol to give crystals of 0.18 g. of(:)3- methoxyestra-2,5(10)-dien-l7-one as crystals melting at 115 C.

Elementary analysis-Calculated for C H O (percent): C, 79.6'8; H, 9.15.Found (percent): C, 79.53; H, 9.22.

(7-2) (i 3-methoxyestra-2,5 10 -dien- 1 7-one In a mixed solution of 2g. cyclohexanone and 50 ml. of toluene, there is dissolved 0.2 g. of(:)3-methoxyestra-2,5(10)-dien-17a-o1 and the resultant solution isconcentrated to 20 m1. To the solution, there is added 0.2 g. ofaluminum isoproproxide and the mixture is refluxed for 3 hours. 30 m1.of water is added to the reaction solution and the mixture, after beingneutralized with dilute sulfuric acid, is subjected to steamdistillation. Then the residue is extracted with ether and the etherlayer, after being washed with Water and dried, is subjected toevaporation to remove the solvent. The residue is recrystallized fromhexane to give 0.1 g. of (i) 3-methoxyestra-2,5(10)-dien-l7-one ascrystals melting at 115 C.

Infrared absorption:

emf- 1743 (:0).

EXAMPLE 2 1*: 3-methoxy-13 fl-ethyl-17a-hydroxy-8, 14- secogona-1,3 ,510) ,9-tetraen-14-one To a solution of 1.3 g. of3-methoxy-l3fiethyl-8,l4- secogona-l,3,5(l0),9-tetraene-14,17-dione in80 m1. of methanol, there is added 0.08 g. of sodium borohydride underice-cooling and the mixture is stirred under the same conditions. After2 hours, Water and ether are added to the reaction solution and theresultant mixture is shaken, followed by separation of ether layer.After the ether layer is washed with water and dried, it is subjected toevaporation to remove the solvent to give 1.3 g. of yellowish oilyresidue of (i)3-methoxyl3fl-ethyl-l7a-hydroxy 8,14 secogona 1,3,5(l0),9-tetraen-14-one. The oil is purified by the chromatography method usingsilica gel.

Infrared absorption:

nu iol mux.

2-1 (i-)3-methoxy-13fl-ethylgona-l,3,5(10) 8, l4-pentaen-17a-ol To asolution of 0.5 g. of (:)3-methoxy-13B-ethyl- 17 a-hydroxy-B,l4-secogona-l,3,5 10 ,9-tetraen-l4-one in 40 ml. of methanol, there isadded 5 drops of concentrated hydrochloric acid and the resultantsolution is left standing for 2 hours at room temperature. Then thereaction solution is shaken with water and ether, followed by separationof the ether layer. After the ether layer is washed with an aqueoussolution of sodium hydrogen carbonate and with water, it is subjected toevaporation to remove the solvent. The residue is subjected to columnchromatography with 20 g. of silica gel and the eluate with a mixture ofbenzene and ether (9: 1) is condensed to give 0.2 g. of(i)3-methoxy-9,14oxido-13fl-ethyl-8,14- secogona-1,3-5(10)-trien-17-one.Melting point: 64 C.

Elementary analysis.-Calculated for C H O (percent): C, 76.43; H, 8.33.Found (percent): C, 76.57; H, 8.33.

To a solution of 0.1 g. of (i)3-methoxy-9,l4-oxido- 1613/3-ethyl-8,l4-secogona-l,3,5(10)-trien-17-one in 10 ml. of methanol,there is added 1 ml. of concentrated hydrochloric acid and the mixedsolution is refluxed for 30 minutes. Then the reaction solution isshaken with a mixture of water and ether, followed by separation of theether layer. After the ether layer is washed with an aqueous solution ofsodium hydrogen carbonate and then with water and dried, the ether layeris subjected to evaporation to remove the solvent and to give 0.1 g. of(i-)3- methoxy-13fi-ethylgona-1,3,5 l0),8,14 pentaen-l7a-ol as yellowishoil.

Ultraviolet absorption:

I'I1,w(e)2 309 (20000).

Infrared absorption:

011014 max.

(2-2) )3-methoxy-13B-ethylgona-1,3,5(10) 8,14-pentaen-l7a-ol To asolution of l g. of(i)3-methoxy-l3B-ethyl-17ahydroxy-8,14-secogona-1,3,5(10),9-tetraen-14-onein 40 ml. of methanol, there is added 10 ml. of concentratedhydrochloric acid and the mixture is refluxed for 30 minutes. Water andether are added to the reaction solution and the resultant mixture isshaken, followed by separation of the ether layer. After the ether layeris washed with an aqueous solution of sodium hydrogen carbonate and withwater and dried, it is subjected to evaporation to remove the solventgiving 0.9 g. of )3-methoxy-13B-ethylgona- 1,3,5 l0),8,14-pentaen-17a-o1 as yellowish oil.

(3) i )3-methoxy-13,3-ethylgona-l,3,5(10) S-tetraen- 1711-01 A solutionof 0.9 g. of (:L-)3-methoxy-13fi-ethylgona-1,3,5(10),8,14-pentaen-17a-ol dissolved in ml. of dioxane is subjectedto catalytic hydrogenation in the presence of 0.5 g. of Raney nickel.Then the reaction solution is subjected to filtration to separate thecatalyst and the filtrate is condensed under reduced pressure toprecipitate crystals of (1:)3-methoxy-13/8-ethylgona-l,3,5(10),8-tetraen-17a-ol. The crystals arerecrystallized from methanol. Melting point: 141-3" C. Yield: 0.6 g.

Elementary analysis.Calculated for C I-1 0 (percent): C, 80.49; H, 8.78.Found (percent): C, 80.36; H, 8.64.

Ultraviolet absorption:

ethanol m,w(e): 29 (16400).

(4) (i)3-methoxy-l3/3-ethylgona-1,3,5(10) trien-17a-ol In a mixture of40 ml. of liquid-ammonia and 10 ml. of dioxane, there is dissolved 0.3g. of (i)3-methoxy-l3fiethylgona-1,3,5(l0),8-tetraen-l7a-ol, and thesolution is cooled to --50 C. To the thus-cooled solution, there isadded 0.5 g. of metallic potassium, followed by stirring for 2 hours. Tothe reaction solution, there is added 2 g. of amomnium chloride and thenthe resultant solution is left standing at room temperature to removeammonia. To the residue, there is added water, followed by extractionwith ether. After the ether layer is washed with water and dried, it issubjected to evaporation to remove the solvent. The residue isrecrystallized from an aqueous solution of methanol to give 0.1 g. of(i)3-methoxy-13 3-ethylgona- 1,3,5(10)-trien-17a-ol as crystals meltingat 71-7 3 C (5) (i)3-methoxy-13B-ethylgona-1,3,5(l0) trien-l'l-one To asolution of 0.02 g. of (:)3-methoxy-139-ethylgona-1,3,5(10)-trien-17a-ol in 5 ml. of acetone, there is added0.2 ml. of an aqueous solution containing 26.72 g. of chromic acidanhydridev and 23 m1. of concentrated l 7 sulfuric acid per 100 ml.,followed by stirring. To the reaction solution, after being leftstanding for 20 minutes at room temperature, there is added water toprecipitate crystals, which are recrystallized from methanol to give0.015 g. of (i)3-methoxy-l3 6-ethylgona-1,3,5(10)-trien- 17-one. Meltingpoint: 128 C.

(6) (i) 3-methoxy-13B-ethylgona-2,5 10) -dien- 17oc-o1 In a mixture ofml. of dioxane, 20 ml. of ether and 100 ml. of liquid ammonia, there isdissolved 0.5 g. of (i)3 methoxy 13B-ethylgona-1,3,5-(10),8-tetraen-17a-01 and the resultant solution is cooled to --50 C. To the solution,there is added 1.2 g. of metallic lithium, followed by stirring. Afterminutes, 20 ml. of ethanol is added dropwise to the reaction solutionand then the resultant solution is left standing at room temperature toremove ammonia. To the residue, there are added Water and ether, and themixture is shaken, followed by separation of the ether layer. After theether layer is washed with water and dried, it is subjected toevaporation to remove the solvent and to give 0.5 g. of (i)3-methoxy-13B-ethylgona-2,5 (10)-dien-17a-ol as orange oil.

(7) 3-n1ethoxy-13fi-ethylgona-2,5 (10)-dien-17-one A solution of 0.2 g.of (i)3-methoxy-13fi-ethylgona- 2,5 (10)-dien-17a-ol in 50 ml. oftoluene is concentrated to about 20 ml. and to the solution, there isadded 0.2 g. of aluminum isopropoxide, followed by refluxing for 3hours. To the reaction solution, there is added water, followed byneutralization With diluted sulfuric acid and by steam distillation. Theresidue is extracted with ether and the ether layer, after being washedwith Water and dried, is subjected to evaporation to remove the solventto give 0.1 g. of -)B-methoxy-13,8-ethylgona-2,5(10)- dien-17-one, whichis recrystallized from other and then from a mixture of ethyl acetateand hexane to give crystals melting at 158-160 C.

Elementary analysis.--Calcu1ated for C H O (percent): C, 80.00; H, 9.33.Found (percent): C, 80.08;

EXAMPLE 3 (1) (i 3-rnethoxy-17a-hydroxy-8,14-secoestra-1,3,5 10),9-tetraenl4-one 17-hydrogensuccinate To a solution of 2 g. of(i-)3-11'16ll1OXY-17a-hYdIOXY- 8,l4-secoestra-1,3,5(10),9-tetraen-14 onein 15 ml. of pyridine, there is added 4 g. of succinic acid anhydrideand the mixture is stirred for 20 hours at 75-80 C. After cooling thereaction solution, Water is added thereto, followed by extracting withether. The ether layer, after being washed with Water and dried, issubjected to evaporation to remove the solvent, To the residue, there isadded a small volume of ethyl acetate to give crystals, which arerecrystallized from ethyl acetate to yield 2.1 g. of (i-)3-methoxy 17ozhydroxy 8,14- secoestra-1,3,5(10), 9-tetraen-14 one 17hydrogensuccinate. Melting point: 121-3 C.

Elementary analysis.Calculated for C H O (percent): C, 68.98; H, 7.04.Found (percent): C, 69.20; H, 6.98.

Ultraviolet absorption:

Infrared absorption:

nu i 01 mux.

cmr 1735, 1718.

(2) Quinine salt of (TL-)3 -methoxy-17u-hydroxy-8,14-secoestra-1,3,5(10),9-tetraen-14 one 17 hydrogensuccinate To a solutionof 3 g. of (i)3-methoxy-17a-hydroxy-8,l4-secoestra-l,3,5(10),9-tetraenl4-one 17 hydrogensuccinate in 25 ml.of acetone, there is added a solution of 2.43 g. of quinine dissolved ina mixture of 20 ml. of acetone and4 ml. of methanol and the resultantsolution is left standing at about 5 C. to precipitate the quinine saltof (:)3 methoxy 17a hydroxy-8,14-secogona- 1,3,5(10),9-tetraen-14 one 17hydrogensuccinate, followed by filtration. The precipitate isrecrystallized from a mixture of methanol and acetone to give 2.1 g. ofcrystals melting at -171" C. (00 i+2 6 (c.=1.0, CHCl The mother liquoris concentrated to give 2.3 g. of oil. (a) 1+118 (c.=1.0, CHCI (33-methoxy-17a-hydroxy-8, l4-secoestra- 1,3,5(10),9-tetraen-14-one In 30ml. of chloroform, there is dissolved 2.2 g. of oil having the opticalactivity 54-118", obtained above (2). The solution is shaken with 20 ml.of 10% sulfuric acid, followed by separation of the chloroform layer,which is extracted twice with 10% sulfuric acid. After the chloroformlayer is washed with water and dried, it is subjected to evaporation toremove the solvent. The residue is dissolved in 20 ml. of methanol andto the solution, there is added 14 ml. of 10 normalaqueous solution ofpotassium hydroxide under ice-cooling, followed by stirring for 1 hour.After addition of water the reaction solution is extracted with ether,and the ether layer, after being washed with water and dried, issubjected to evaporation to remove the solvent. The residue isrecrystallized from a mixture of methanol and water to give 0.8 g. of(-)3-methoxy-17a-hydroxy-8,14- secoestra-1,3,5(10),9-tetraen-14-one asneedles melting at 102-103" C. (00 -83.6 (c.=1.0, CHClg).

From 1.4 g. of crystals having the optical activity of ((1) i+26,prepared above (2), there is obtained in the same manner as above 0.5 g.of (+)3-methoxy-17a-hydroxy-8,14=secoestra-1,3,5(10),9-tetraen-14-one ascolorless needles melting at 102l04 C. (00 {4-81.6" (c.=1, CHCI (4)(-)3-methoxyestra-1,3,5(10), 8,14-pentaen-17a-ol To a solution of 0.6 g.of ()3-methoxy-17a-hydroxy- 8,l4-secoestra-1,3,5(10),9-tetraen-14-one in16 ml. of methanol, there is added 2.7 ml. of concentrated hydrochloricacid and the mixture is refluxed for 40 minutes under moderate stirring.The reaction solution is poured into the water and extracted withbenzene, followed by separation of the benzene layer. After being Washedwith water and dried, the benzene layer is subjected to evaporation toremove the solvent, followed by allowing the residue to stand at roomtemperature to precipitate crystals, which are recrystallized from asmall amount of methanol to give 0.55 g. of ()3 methoxyestra-1,3,5(1-0),8,14-pentaen-17u-ol as colorless needles melting at 63-64 C.(00

From 0.45 g. of (+)3-methoxy-17a-hydroxy-8,14-secoestra-1,3,5(10),9-tetraen-14-one, there is obtained in the samemanner as above 0.4 g. of (+)3-methoxyestra-1,3,5(10),8,14-pentaen-17a-ol as crystals melting at 63 64 C. (00 +190.8(c.=0.5, CHCl;,).

(5) 3-methoxyestra- 1,3,5 10) ,8 tetraenl7u-ol To a solution of 0.6 g.of ()3 methoxyestra- 1,3,5(l0),8,14-pentaen-17a-ol in 30 ml. of dioxane,there is added 0.4 g. of Raney nickel. The mixture is shaken in ahydrogen gas stream until 47 ml. of hydrogen gas is absorbed. Then thecatalyst is filtered oif and the filtrate is concentrated to givecrystals. The crystals are recrystallized from ether to give 0.5 g. of()3-methoxyestra 1,3,5(10),8-tetraen-l7a-ol as plates melting at 113-116C. (00 31.5 (c.=l.'0, CHCl From 0.45 g. of(+)3-methoxyestra-1,3,5(10),8,14- pentaen-17a-ol, there is prepared inthe same manner as above 0.4 g. of(+)3-methoxyestra-1,3,5(10),8-tetraen- 17oc-0l. (00 +41.3 (c.=1.0, CHCI1 9 (6) (+)3-methoxyestra-1,3,5(10)-trien-l7a-ol In a mixture of 20 ml.of dioxane, 40 ml. of tetrahydrofuran and 250 ml. of liquid ammonia,there is dissolved 0.4 g. of ()3-methoxyestra-1,3,5(l0),8-tetraen-17cc-Ol. j+41.3 (c.=1.0, CHCl potassium under cooling at 30-50 C.,followed by stirring for 2 hours. To the reaction solution, there isadded ammonium chloride to decompose excess potassium. So-treatedreaction solution is then allowed to stand at room temperature to removeliquid ammonia completely. The residue is dissolved in water, and themixture is extracted with benzene. The benzene layer, after being washedwith Water and dried, is subjected to evaporation -to remove thesolvent. The solid residue is recrystallized from a mixture of water andethanol to give 0.35 g. of (+)3-methoxyestra-1,3,5(10)-trien-17oz-ol asneedles melting at 96100 C. (00 i |17.6 (c.=0.5, CHCl From 0.4 g. of(+)3-methoxyestra-1,3,5(10),8- tetraen-l7wol, there is prepared in thesame manner as above 0.33 g. of (-)3-methoxyestra-1,3,5(10)-trien-17oc-01 as crystals melting at 9699 C. (00 17.6 (c.=0.5, CHClg).

(7) 3-1116lll10XY8St1121- 1,3,5 10) -trien- 1 7-one To a solution of 0.2g. of (+)3-methoxyestra- 1,3,5 (10)-trien-17a-ol in 20 ml. of acetone,there is added gradually 0.25 ml. of an aqueous solution containing26.72 g. of chromic acid anhydride and 23 ml. of concentrated sulfuricacid per 100 ml. followed by shaking. To the reaction solution, there isadded methanol to decompose excess chromic acid. The resultant solutionis diluted with water to precipitate crystals, which are separated byfiltration. After being washed with water, the crystals arerecrystallized from ethanol to give 0.2 g. of 3-methoxyestra-1,3,5(10)-trien 17 one. Melting point: 165168 C. (00 +167 (c.=1, CHCl From0.3 g. of ()3-methoxyestra-1,3,5 (10)-trien- 17oc-01, there is preparedin the same manner as above 0.25 g. of()3-methoxyestra-1,3,5(10)-trien-17-one.

Melting point: 162168 C. (00 147.6 (c.: 1, CH'Cl EXAMPLE 43-methoxy-8,14-secoestra-1,3,5 10) ,9-tetraen-14,17- dione In a solutioncontaining 20 ml. of dimethylsulfoxide, 7 g. ofdicyclohexylcarbodiimide, 9.6 ml. of pyridine, 0.48 ml. oftrifluoroacetic acid and 18 ml. of benzene, there is dissolved 3.6 g. of(+)3-methoxy-17a-hydroxy-8,14- secoestra-l,3,5(10),9-tetraen-l4-one andthe resultant solution is allowed to stand at room temperatureovernight. After ether is added to the reaction solution, methanolsolution of oxalic acid is added and the mixture solution is allowed tostand until bubbling ceases.

To the resultant solution, there is added Water to precipitatedicyclohexylurea, which is filtered off. After being washed with water,the ether layer is subjected to evaporation to remove the solvent. Theoily residue is chromatographed on a column of silica gel, and 3 g. of3-methoxy- 8,14-secoestra-1,3,5(10),9-tetraene14,l7-dione is separatedfrom the eluate with a mixture of benzene and ether. Melting point: 78C.

EXAMPLE (1) l-menthoxyacetate of i 3-methoxy-17a-hydroxy-8,14-secoestra-1,3,5( l0) ,8-tetraen-14-one To a mixture of 0.4 g. of(:)3-methoxy-17a-hydroxy- 8,14-secoestra-l,3,5( ),9(l1)-tetraen-l4-onedissolved in a mixture of 0.13 ml. of pyridine and 1.5 ml. of dioxane,there is added 0.37 g. of l-menthoxyacetyl chloride. The whole mixtureis allowed to stand at room temperature overnight. To the reactionsolution, there is added water and then the aqueous solution isextracted with ether. The

ether layer, after being washed with water and dried, is subjected toevaporation to remove the solvent. The residue is subjected tochromatography on a column of 20 g. of silica gel, and from the eluatewith a mixture of benzene and ether (4:1), there is obtained 0.7 g. ofl-menthoxyacetate of3-methoxy-17a-hydroxy-8,14-secoestra-1,3,5(l0),8-tetraen-l4-one ascolorless oil.

The menthoxyacetate is dissolved in hot methanol and the solution iscooled at -40 C. to separate oil, which is purified by repetition ofdissolving in hot methanol and cooling several times. Thus-obtainedcolorless oil is allowed to stand under cooling to precepitate crystals.The crystals are recrystallized from methanol to give 0.12 g. ofl-menthoxyacetate of (+)3-methoxy-17u-hydroxy- 8, l4-secoestra-l,3,5 10),8-tetraen-l4-one. Melting point: 88-90 C. (00 3 (c.=0.5, CHCl Thecombined mother liquor is concentrated to give 0.4 g. ofl-menthoxyacetate of()3-methoxy-l7a-hydroxy-S,14-secoestra-1,3,5(10),8-tetraen-14-one ascolorless oil. (a) 50.3 (c.=0.5, CHCl (2)3-methoxy-l7a-hydroxy-8,l4-secoestra-l,3,5( l0) ,8- tetraenl 4-one To asolution of 0.1 g. of l-menthoxyacetate of (+)3- methoxy 17oz hydroxy8,14 secoestra-1,3,5(l0),8- tetraen-14-one in 5 ml. of ethanol is added1 ml. of ethanol solution of l-normal potassium hydroxide, followed bystirring for 20 minutes at room temperature. To the reaction solution,there is added water and the resultant solution is extracted with ether.The ether layer, after being washed with water and dried, is subjectedto evaporation to remove the solvent to give 0.07 g. of (+)3-methoxy-17ahydroxy 8,14 secoestra-l,3,5(l0),8-tetraen-14-one as paleyellowish oil. (a);, +48 (c.=l.0,

CHC1

Infrared absorption:

CHCI; max. cm. :3500(OH), 1730(C O), 1605, 1568, 1490 (aromatic ring).

From 0.3 g. of l-menthoxyacetate of (-)3-methoxy- 17a-hydroxy 8,14secoestra-1,3,5(10),8-tetraen-14-one, there is prepared in the samemanner as above 0.15 g. of (-)3-methoxy-17a-hydroxy 8,14 secoestra-1,3,5(10), 9-tetraen-14-one. (cc) 48 (c.=1.0, CHCl Infrared absorption:

CHICl max. 3

cm." :3500(OH), 1730(C=O), 1605, 1568, 1485 (aromatic ring).

(3) ()3-methoxyestra-1,3,5(10),8,l4-pentaen-17a-ol Thus-obtained(-)3-methoxy-1h-hydroxy-8,l4-secoestra-l,3,5(10),9-tetraen-14-one isconverted to ()3 methoxyestra-1,3,5(10),8,14-pentaen-17a-ol in the samemanner as in "Example 3(4).

(4) 3-methoxy-8,14-secoestra-1,3,5(10),9-tetraene- 14,17-dione To asolution of 0.05 g. of (+)3-methoxy-l7a-hydroxy-8,14-secoestra-1,3,5(l0),9-tetraen-l4-one in 5 ml. of acetone, there isadded 1 ml. of an aqueous solution containing 26.72 g. of chromic acidanhydride and 23 ml. of concentrated sulfuric acid per ml., followed byshaking. The reaction solution is extracted with ether. After the etherlayer is washed with an aqueous solution of sodium hydrogen carbonateand then with water and dried, it is subjected to evaporation to removethe solvent and to give 0.045 g. of (i)3-methoXy-8,14-secoestra-1,3,5(10),9-tetraene-14,17-dione.

EXAMPLE 6 (l) 17a-acetoxy-3-methoxy-8,14-secoestra-1,3,5(10),9-tetraen-14-ol In 100 ml. of methanol, there is dissolved 2.4g. of (-)17a-acetoxy 3 methoxy-S,14 secoestra1,3,5(10),9-

ill; cm.* :3450(OH), 1730(ester), 1605, 1570, 1495 (aromatic ring). a

(2) 17 a-acetoxy-3-methoxy-9, 1 4-oxido-8, l4- secoestra-1,3,5 -triene Asolution of 2.4 g. of ()17u-acetoxy-3-methoxy-8,l4-secoestra-1,3,5(10),9-tetraen-14-ol dissolved in 100 ml. of benzeneis concentrated to 10 ml. On the other hand, a solution of 0.1 g. ofpara-toluenesulfonic acid dissolved in 100 ml. of benzene isconcentrated to 10 ml., to which the former solution is then added,followed by allowing to stand for 30 minutes at room temperature. Thereaction solution is shaken with an aqueous solution of sodium hydrogencarbonate, followed by separation of the benzene layer. After thebenzene layer is washed with water and dried, it is subjected toevaporation under reduced pressure to remove the solvent. The residue ispurified by chromatography on a silica gel column, and from benzeneeluate, there is obtained 2.3 g. of ()17ocacetoxy-S-methoxy 9,14oxido-8,14-secoestra-1,3,5(10)- triene as colorless oil. (a) -20.8(c.=1, chloroform).

Infrared absorption:

cm. :1730(ester), 1610, 1575, 1500 (aromatic ring).

Ultraviolet absorption:

ethu. 01 km...

1'I1,u (6)2277 (1820), 283 (1720). I

(3) (-)3-methoxy-9,14-oxido-8,14-secoestra- 1,3,5(10)-trien-17-ol To asolution of 2.3 g. of ()17a acetoxy 3 methoxy 9,14 oxido 8,14 secoestra1,3,5(10) triene in 30 ml. of ethanol, there is added 20 ml. of ethanolsolution of l-normal potassium hydroxide, followed by stirring for onehour at room temperature. To the reaction solution, there is added waterand the mixtureis extracted with ether. After the ether layer is Washedwith water and dried, it is subjected to evaporation to remove thesolvent and to give 1.9 g. of 3 methoxy 9,14- oxido 8,14 secoestra1,3,5(10) trien 17 01 as colorless oil.

Infrared absorption:

illi... cm.- :3400(OH), 1610, 1580, 1500 (aromatic ring).

(4 (+)3-methoxy-9,14-oxido-8,14-secoestra- 1,3,5 10) -trien-17-one To asolution of 2 g. of chromic acid anhydride in 30 ml. of pyridine, thereis added a solution of 1.9 g. of ()3 methoxy 9,14 oxido 8,14 secoestra-1,3,5(10)-trien-17-ol dissolved in 10 ml. of pyridine, followed bystirring for 30 minutes at roomtemperature. The reaction solution ispoured into water and the mixture is extracted with ether. The etherlayer is washed with diluted sulfuric acid, with an aqueous solution ofsodium hydrogen carbonate and then with water, and dried, followed byconcentration to give 1.65 g. of (+)3- methoxy 9,14 oxido 8,14 secoestra1,3,5(10)- trien 17 one as the residue which is then purified bychromatography to obtain crystals melting at 77-80 C. (00 +35 (c.= 1,chloroform).

Infrared absorption:

' nllit ll xethanol (5) (+)3-methoxyestra-1,3,5(10),8,14- pentaen-170mlTo a solution of 1.4 g. of (+)3-methoxy-9,14-oxido-8, 14 secoestra1,3,5(10) trien 17 one in 30 m1. of methanol, there is added 5 ml. ofconcentrated hydrochloric acid, followed by refluxing for 30 minutes. Tothe reaction solution, there is added water and the mixture is extractedwith ether. The ether layer is washed with an aqueous solution of sodiumhydrogen carbonate and with water and dried, and then subjected toevaporation to remove the solvent. From the residue, there is obtained1.2 g. of (+)3 methoxyestra 1,3,5(10),8,14- pentaen 17a 01 as crystalsmelting at 6066 C. (00 +194 (c.=1, chloroform).

Infrared absorption:

All.

cm.* :3400(OH).

Ultraviolet absorption:

was?

In,u(e)i 3.11.

EXAMPLE 7 (+)3-methoxy-l3-ethylgona-1,3,5(10),8,14- pentaen-17a-ol To asolution of 1 g. of )3-methoxy 9,14 oxidol3 ethyl 8,14 secogona1,3,5(10) trien 17 one in 40 m1. of methanol, there is added 10 ml. ofconcentrated hydrochloric acid, followed by refluxing for one hour. Tothe reaction solution, there is added water and the mixture is extractedwith ether. The ether layer is washed with an aqueous solution of sodiumhydrogen carbonate and then with water and dried, and subjected toevaporation to remove the solvent to give about 1 g. of (:)3 methoxy 13ethylgona 1,3,5(10),8,14- pentaen 17a 01 as oil.

Ultraviolet absorption:

ethanol Illam,u. (e) :310 (24000).

EXAMPLE 8 (1) 17a-hydrogensuccinoyloxy-3-methoxy-8,14-secoestra-1,3,5(10),9-tetraen-14-ol To a solution of 2.2 g. of(+)17a-hydrogensuccinoyloxy 3 methoxy 8,14 secoestra 1,3,5 (10),9tetraen- Home in a mixture of 5 ml. of pyridine and 5 m1. of water,there is added 0.1 g. of sodium borohydride under cooling at --10-0 C.,followed by stirring. After one hour, water is added to the reaction andthe mixture is adjusted to about pH 5 with hydrochloric acid, followedby extraction with ether. After the ether layer is washed (2)3-methoxy-9,14-oxido-8,14-secoestra- 1,3,5(10)-trien-17-ol Thus-obtained(+)17a hydrogensuccinoyloxy-3-methoxy 8,14 secoestra 1,3,5(10 ),9tetraen 14 ol 23 is converted to 1 g. of (+)3 methoxy 9,14 oxido- 8,14secoestra 1,3,5(10) trien 17 01 in the same manner as in Example 6(2)and (3).

(3) 3 -methoxy-9,14-oxido-8,14 secoestra- 1,3 ,5 10 -trien-l 7-0neThus-obtained (+)3 methoxy 9,14 oxido 8,14- secoestra 1,3,5(10) trien 1701 is converted to 0.8 g. of (-)3 methoxy 9,14 oxido 8,14 secoestra-1,3,5(10) trien 17 one as oil in the same manner as in Example 6(4).--35 (c.=1, chloroform).

(4) ()3-methoxyestra-1,3,5(10),8,14-pentaen-17a-ol Thus-obtained ()3methoxy 9,14 oxido 8,14- secoestra 1,3,5(10) trien 17 one is convertedto 0.8 g. of ()3-methoxyestra 1,3,5(10),8,14 pentaen- 1704-01 as oil inthe same manner as in Example 6(5), and is recrystallized from methanolto give needles melting at 6364 C. (00 --200.

EXAMPLE 9 3-methoxyestra-2,5 (10)-dien-17-one (-)3 methoxyestra1,3,5(10),8 tetraen 17a 01 obtained in Example 3(5) is converted to(+)3-methoxyestra 2,5 (10) dien 17a 01 in the same manner as in Example1(6). Thus-obtained dienol is further converted to (+)3 methoxyestra 2,5(10) dien 17 one in the same manner as in Example 1 (7-1). Meltingpoint: 1236 C.

Infrared absorption:

nuiol max.

(cm.* ):1740 (carbonyl radical); 1700, 1667 (double bond).

Having thus disclosed the invention, what is claimed 1. In a method forthe total synthesis of 3-methoxy 13- substituted 17 oxygenatedgona-1,3,5(10)-triene starting from 3-methoxy 13-substituted8,14-secogona-1,3,5(10),9- tetraene-14,17-dione, the substituent at the13-position being a hydrocarbon group having at most 7 carbon atoms, theimprovement which comprises (1) first reducing said 3-methoxy13-substituted 8,14-secogona-1,3- (10),9-tetraene-14,17-dione with amember selected from the group consisting of metallic hydride complexesand aluminum alkoxides, each alkyl of the alkoxide having at most 4carbon atoms, to produce, as a racemic mixture, the corresponding3-methoxy 13-substituted 17ahydroxy-8,14-secogona-1,3,5(),9-tetraen-17one, and then (2) subjecting the so-obtained product to ring-closure,under strongly acidic conditions to produce the corresponding 3-methoxy13-substituted gona-1,3,5(10) 8,14-pentaen-17a-o1.

2. In a method for the total synthesis of 3-methoxy 13- substituted17-oxygenated gona-1,3,5(10)-triene starting from 3-methoxy13-substituted 8,14-secogona-1,3,5(10),9- tetraene-14,17-dione, thesubstitutent at the 13-position being a hydrocarbon group having at most7 carbon atoms, the improvement which comprises (1) first reducing said3-methoxy 13-substituted 8,14-secogona-1,3- 5(10),9-tetraene-14,17-dionewith a member selected from the group consisting of metallic hydridecomplexes and aluminum alkoxides, each alkyl of the alkoxide having atmost 4 carbon atoms, to produce, as a racemic mixture, the corresponding3-methoxy 13-substituted 17a-hydroxy 8,14secogona-1,3,5(10),9-tetraen-l7-ones, (2)

subjecting the racemic mixture to optical resolution into an isomerhaving the configuration of the formula R 9 1 ol CH O- Q where R is thesubstituent at the 13-position, and its antipode, and then (3)subjecting the optically active isomer of the configuration of Formula Ito ring-closure under strongly acidic conditions to produce opticallyactive 3- methoxy 13-substituted gona-1,3,5(10),8,14-pentaen- 17a-ols.

3. The improvement according to claim 2, wherein the antipode of thecompound having the configuration of Formula I is subjected to thefollowing sequence of reaction steps:

(1) step of allowing the antipode to react with an acylating agent toproduce optically active 3-methoxy 13 substituted 17a acyloxy8,14-secogona 1,3- 5 10 ,9-tetraen-14-one;

(2) step of reducing the so-obtained compound with a metallic complex;

(3) step of subjecting the so-obtained compound to mild or stronglyacidic conditions to produce optically active 3-methoxy 13-substituted17a-acyloxy-9,14- oxide-8, 14-secogona-1,3,S( 10) ,9-tetraene;

(4) step of subjecting to so-obtained compound to hydrolysis in thepresence of an alkali catalyst to produce optically active 3-methoxy13-substituted-9,14- oxido-8,14-secogona-1,3,5(10),9-tetraen-17-ol;

(5) step of subjecting the so-obtained compound to oxidation to produceoptically active 3-methoxy 13- substituted 9,14oxide-8,14-secogona-1,3,5(10),9- tetraen-17-one; and

(6) step of subjecting to so-obtained compound to strongly acidicconditions to produce the same optically active 3-methoxy 13-substitutedgona-1,3,5(10), 8,14-pentaen-17-0l as the product from the isomer havingthe configuration of Formula I,

whereby no loss of the 3-methoxy 13-substituted17a-hydroxy-8,14-secogona-1,3,5(10),9-tetraen-17-one is entailed.

4. The improvement according to claim 2, wherein the antipode of thecompound having the configuration of the Formula I is subjected tooxidation to regain the starting 3 methoxy 13-substituted 8,14secogona-1,3- 5(10),9-tetraene-14,17-dione.

References Cited UNITED STATES PATENTS 3,391,165 7/1968 Hughes et al.260397.4

3,407,217 10/1968 Hughes et al 260397.4

FOREIGN PATENTS 991,593 5/1965 England 260397.4

1,010,051 11/1965 England 260-397.4

ELBERT L. ROBERTS, Primary Examiner U.S. Cl. X.R.

